Fighting hypoxia to improve photodynamic therapy-driven immunotherapy: Alleviating, exploiting and disregarding

Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments. Photodynamic therapy (PDT) is one such treatment, which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death (ICD). However, the effectiveness of PDT in enhancing immune responses is influenced by factors, such as photosensitizers and the tumor microenvironment, particularly hypoxia. Current clinically used PDT heavily relies on oxygen (O₂) availability and can be limited by tumor hypoxia. Additionally, the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells. Meanwhile, the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions. Consequently, numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT, aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy. This review investigates these strategies, including approaches to alleviate, exploit, and disregard tumor hypoxia within the context of PDT/immunotherapy. It also emphasizes the role of advanced nanomedicine and its benefits in these strategies, while outlining current challenges and future prospects in the field.